The present invention relates to a treatment for diabetes which combines an immunoregulator and a .beta. cell proliferation agent and, in particular, which includes both Linomide and the reg protein.
Diabetes mellitus is particularly characterized by hyperglycemia, although other related clinical manifestations include vascular complications and altered metabolism of lipids, proteins and carbohydrates. For example, the altered metabolism of lipids can lead to increased production of ketones, potentially leading to ketonemia and acidosis. Vascular changes which occur include the thickening of the capillary basement membrane, leading to narrowing of the lumen of blood vessels and reduced blood circulation. Such reduced circulation can, in turn, cause retinopathy, neuropathy and gangrene of the extremities. Thus, diabetes mellitus has consequences which extend far beyond hyperglycemia.
Diabetes mellitus can be divided into two clinical syndromes, Type I and Type II diabetes mellitus. Type I, or insulin-dependent diabetes mellitus (IDDM), is a chronic autoimmune disease characterized by the extensive loss of .beta. cells in the pancreatic Islets of Langerhans (hereinafter referred to as "islets"), which produce insulin. As these cells are progressively destroyed, the amount of secreted insulin decreases, eventually leading to hyperglycemia (abnormally high level of glucose in the blood) when the amount secreted drops below the level required for euglycemia (normal blood glucose level). Although the exact trigger for this immune response is not known, patients with IDDM have high levels of antibodies against pancreatic .beta. cells. However, not all patients with high levels of these antibodies develop IDDM.
One possible explanation for this apparent discrepancy is the capacity of the pancreas to expand .beta. cell mass through proliferation of these cells. For example, at the onset of IDDM, the pancreas has been shown to be capable of neoformation of islets W. Gepts and P. M. Lecompte, Am. J Med., 70:105-115, 1981!. .beta. cell proliferation and regeneration has also been demonstrated in animal models of diabetes with reduced .beta. cell mass, and in transgenic mice with .beta. cell damage S. Bonner-Weir et al., Diabetes, 42:1715-1720, 1993; D. Gu and N. Sarvetnick, Development, 118:33-46, 1993!. Unfortunately, the lack of significant proliferative ability of mature .beta. cells is a major impediment to the treatment of diabetes, particularly due to the relatively late diagnosis of the disease.
Patients with IDDM are usually diagnosed when clinical symptoms are manifested, such as hyperglycemia. However, by the time such symptoms are apparent, the disease has been progressing over an extensive period of time and extensive loss of pancreatic .beta. cells has occurred. Therefore, treatments such as immunoregulators, which seek to inhibit the autoimmune response, can only arrest further progress of IDDM and cannot reverse the extensive pancreatic cell loss. Unless the lost .beta. cells are replaced, the patient will continue to experience clinical symptoms of IDDM, even as the course of the disease itself is halted. Thus, a successful treatment for IDDM must both halt the further progression of the disease and induce the replacement of lost pancreatic .beta. cells.
There is therefore an unmet medical need for a treatment for diabetes which both halts the further progress of the disease and which ameliorates or reverses clinical symptoms by inducing the proliferation of pancreatic .beta. cells.